ABSTRACT Genetic variation between men and women predisposes differences in their responses to infection. For example, women respond much more vigorously to agents and vaccines including influenza, toxoplasmosis, and legionella, and are more prone to developing autoimmune disorders including Grave's disease, rheumatoid arthritis, and systemic lupus erythematosis (SLE). The molecular bases of sex differences in immunity and diseases of the immune system are unknown, although the presence of key immune modulatory genes on the X chromosome suggests a basis for sex-specific responses. The importance of sex-specific factors has been recognized by the National Institutes of Health, which changed its policies to require investigators to address and report differences between the sexes in pre-clinical studies. In this regard, we have observed that mature mIg+ B cells of mice express high levels of Serine/Arginine-specific Protein Kinase 3, a PKC-like kinase encoded by an X-linked gene. We propose that SRPK3 regulates humoral immunity in humans and mice. Using mice with floxed Srpk3 genes that delete specifically in B cells (using Cd79a-Cre), we observed that SRPK3 is necessary for efficient T-independent (TI) type 2 antibody responses against the model antigen NP-Ficoll. Preliminary experiments also suggest graded antibody responses in female mice with different gene dosage of Srpk3 (Srpk3+/+, Srpk3+/?, and Srpk3?/?). We hypothesize that SRPK3 is required for appropriate antibody responses, which are disrupted in its absence due to aberrant pre-mRNA splicing and the lack of SRPK3-mediated phosphorylation. To address this hypothesis, we will determine requirements for SRPK3 in responses to model antigens and identify targets of the kinase in pre-mRNA splicing and the phosphorylated proteome in marginal zone B cells. We conclude that the loss of SRPK3 function results in significant immunodeficiencies in males and females.